Three-hybrid ionic iridium (III) complex based on diphosphine-containing ligand and anti-tumor application of three-hybrid ionic iridium (III) complex

Abstract

The invention discloses a tri-hybrid ionic iridium (III) complex containing a diphosphine ligand and an anti-tumor application thereof, and belongs to the technical field of crossing of metal organic complex design and tumor drugs. By introducing a large-rigidity ligand, a traditional two-heteroligand iridium complex is converted into a three-heteroligand complex with a more stable structure, the complex can keep the structure complete in a physiological environment, the drug stability is ensured, in-vivo transmission and absorption are efficient, and the bioavailability is remarkably improved; the compound shows a strong inhibition capability on a plurality of tumor cell lines, the IC50 value is far lower than that of a traditional drug, the toxic effect is excellent, and the universality is strong; the iridium (III) center and the diphosphine ligand in the complex synergistically exert anti-tumor activity to form a'metal-ligand 'synergistic anti-cancer mechanism, and the complex is sensitive to malignant tumor microenvironment, can specifically release iridium ions and overcome tumor drug resistance, provides candidate molecules for development of novel anti-cancer drugs, and has wide application prospects.

Description

Technical Field

[0001] The present invention belongs to the cross field of metal organic complex design and tumor drugs, and relates to a tri-hybrid ion-type iridium (III) complex based on a diphosphine ligand and its anti-tumor application. Background Art

[0002] In the field of cancer treatment, traditional anticancer drugs have long played an important role, but their limitations are becoming increasingly prominent. Platinum drugs, represented by cisplatin, are milestones in early anticancer drugs. They inhibit the proliferation of tumor cells by cross-linking with DNA, interfering with DNA replication and transcription. However, this type of drug has many disadvantages in clinical application. For example, cisplatin has strong nephrotoxicity, neurotoxicity, and ototoxicity, which seriously limits its dosage and applicable population. In addition, traditional platinum drugs such as cisplatin inevitably damage healthy cells, causing patients to suffer serious side effects during anticancer treatment, such as nausea, vomiting, and hair loss, which greatly reduces the quality of life of patients. Moreover, tumor cells gradually develop resistance to traditional platinum drugs, causing the efficacy of the drugs to weaken over time. New anticancer drugs are urgently needed to overcome this dilemma.

[0003] The emergence of iridium complexes offers new opportunities and important research directions for the development of anticancer drugs. Their unique advantages stem from the unique electronic structure and coordination chemistry of iridium metal. Iridium complexes can interact with biomacromolecules in a variety of coordination modes, for example, by base pairing with DNA or binding to specific amino acid residues in proteins, achieving precise targeting of tumor cells. Related literature (Chen L, Tang H, Chen W, et al. Mitochondria-targetedcyclometalated iridium (III) complexes: Dual induction of A549 cellsapoptosis and autophagy[J]. Journal of Inorganic Biochemistry, 2023, 249:112397; Zhang HW, Tian L, Xiao RX, et al. Anticancer Effect Evaluation InVitro and In Vivo of Iridium (Ⅲ) Polypyridyl Complexes Targeting DNA andMitochondria[J]. Bioorganic Chemistry, 2021, 115: 105290; Xiong K, Chen Y, Ouyang C, et al. Cyclometalated iridium(Ⅲ) complexes as mitochondria -targeted anticancer agents[J]. Biochimie, 2016, 125: 186-194; Zhang C, Guan RL, Liao XX, et al. Mitochondrial DNA Targeting and Impairment by a DinuclearIr-Pt Complex that Overcomes Cisplatin Resistance[J]. Inorganic ChemistryFrontiers, 2020, 7(9): 1864-1871) points out that iridium complexes can induce cell apoptosis and autophagy, and their mechanisms of action are diverse, including the production of reactive oxygen species (ROS), destruction of mitochondrial membrane potential, and covalent or non-covalent interactions with DNA.Furthermore, iridium complexes are highly structurally designable. Their octahedral coordination field allows for the introduction of multiple ligand types (e.g., C^N-type aromatic heterocyclic ligands, P^P-type phosphine ligands, etc.). Through electronic and steric interactions between ligands, the redox potential, excited-state lifetime, and biodistribution characteristics of the complex can be synergistically modulated, thereby optimizing drug efficacy and safety. Compared with traditional platinum drugs, iridium complexes exhibit significant differences in anti-tumor spectrum, pharmacokinetics, and toxicity. Some iridium complexes still exhibit potent inhibitory effects against cisplatin-resistant cancer cell lines. Their unique cytotoxic mechanism gives them a potential advantage in overcoming tumor resistance.

[0004] Ir(CN)2(PP)-type anti-tumor drugs, commonly used in current research, are diheteroleptic iridium complexes containing bisphosphines. Research has primarily focused on the modification and adaptation of the PP ligand. While these diheteroleptic iridium complexes with bisphosphines exhibit some anticancer activity, they face several challenges: First, the universality of their cytotoxicity to tumor cells; second, their relatively simple structure, lacking sufficient steric hindrance and structural diversity, results in limited stability in physiological environments. In complex physiological systems, their relatively flexible structure makes them susceptible to interference from biomolecules, affecting their binding efficiency and selectivity to tumor cell targets. Furthermore, the mechanism of action of Ir(CN)2(PP) diheteroleptic drugs is relatively simple, relying primarily on the coordination of the CN ligand with the iridium center and the simple interaction of the PP ligand with DNA. This makes it difficult to achieve synergistic attack on multiple tumor cell targets and can easily lead to drug resistance in tumor cells. Summary of the Invention

[0005] In view of the problems that existing anticancer drugs based on diheterolactic iridium complexes containing bisphosphine have, such as insufficient universality of toxicity to tumor cells, limited stability in physiological environments, susceptibility to interference from biological molecules, low binding efficiency and selectivity, a single mechanism of action, and susceptibility to drug resistance in tumor cells, the present invention aims to provide trihybrid ionic iridium (III) complexes based on diphosphine ligands and their antitumor applications.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions: The present invention provides a tri-hybrid ionic iridium (III) complex containing a diphosphine ligand, wherein the tri-hybrid ionic iridium (III) complex has the following structural formula: ; Among them, C 1 ^N 1 The ligand is selected from any one of the rigid ligands Hiqbt, dpbq and tpbz; C 2 ^N 2The ligand is selected from any one of ppy, dfppy and mppy ligands; The P^P ligand is selected from any one of a rigid group or a flexible group, wherein the rigid group is a phenyl group or a naphthyl group, and the flexible group is an ethylene group or a propylene group.

[0007] The P^P ligand is any one of 1,2-bis(diphenylphosphino)benzene (dppb), 1,2-bis(diphenylphosphino)ethane (dppe), and 1,3-bis(diphenylphosphino)propane (dppp).

[0008] Furthermore, the tri-hybrid ionic iridium (III) complex has the following structural formula: .

[0009] The present invention provides a method for preparing the above-mentioned trihybrid ionic iridium (III) complex containing a diphosphine ligand, comprising: Step 1, C 1 ^N 1 Ligand, C 2 ^N 2 The ligand and iridium chloride trihydrate are mixed for reaction, cooled, precipitated and dried to obtain a dichloro bridged intermediate mixture containing the target bridged intermediate [Ir(C 1 ^N 1 )(C 2 ^N 2 )(μ-Cl)]2 Step 2: Under nitrogen protection, the dichloro bridged intermediate mixture is mixed with the P^P auxiliary ligand for reaction, cooled, and ammonium hexafluorophosphate is added and stirred to react to obtain a trihybrid ionic iridium (III) complex containing a bisphosphine ligand.

[0010] In step 1, the C 1 ^N 1 Ligand, C 2 ^N 2 The molar ratio of the ligand and iridium chloride trihydrate is (2~3):(2~3):1.

[0011] In step 1, the reaction temperature is 100-120° C., and the reaction time is 40-60 h.

[0012] In step 1, the precipitant is a saturated salt solution.

[0013] Furthermore, in step 1, the drying temperature is 40-60° C., and the drying time is 10-14 h.

[0014] In step 2, the molar ratio of the dichloro bridged intermediate mixture to the P^P auxiliary ligand is 1:2-3, the reaction temperature is 50-60° C., and the reaction time is 20-26 h.

[0015] Furthermore, in step 2, the stirring reaction temperature is 23-27° C., and the reaction time is 10-14 h.

[0016] The present invention provides a pharmaceutical composition, which contains the tri-hybrid ionic iridium (III) complex containing a bisphosphine ligand.

[0017] The pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0018] The carrier is selected from fillers, disintegrants, binders, lubricants or combinations thereof.

[0019] Furthermore, the filler is selected from starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate or a combination thereof; the disintegrant is selected from carboxymethyl cellulose and its salts, cross-linked carboxymethyl cellulose and its salts, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or a combination thereof; the binder is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, starch slurry or a combination thereof; the lubricant is selected from magnesium stearate, calcium stearate or a combination thereof.

[0020] The use of the trihybrid ionic iridium (III) complex containing a bisphosphine ligand or the pharmaceutical composition in the preparation of anti-tumor drugs.

[0021] The tumor is any one or more of lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, prostate cancer, and ovarian cancer.

[0022] The anti-tumor drug is used to inhibit the proliferation of tumor cells.

[0023] The anti-tumor drug is used to induce apoptosis of tumor cells.

[0024] Compared with the prior art, the present invention achieves the following technical effects: The application provides a double-phosphine ligand-based triple-hybrid ionic iridium (III) complex, which is based on an Ir(C^N)2(P^P) type anti-tumor drug, and a rigid ligand such as Hiqbt, dpbq and tpbz is innovatively introduced to change the double-hybrid iridium complex into a triple-hybrid complex with a more stable structure. The rigid ligand limits the free rotation of the ligand around the iridium center through a strong coordination bond and a steric hindrance effect, and the structural stability of the complex in a physiological environment is significantly enhanced. Compared with a traditional double-hybrid iridium complex, the triple-hybrid rigid structure can reduce non-specific interactions, ensure that the complex does not easily change in structure during in-vivo transmission and action, and thus improve the stability and bioavailability of the drug. The traditional double-hybrid iridium complex has a single action mechanism (depending on the coordination of the CN ligand with the iridium center and the simple interaction of the PP ligand with DNA), and is easy to cause drug resistance of tumor cells. The triple-hybrid rigid structure can reduce the risk of drug resistance through multi-target synergistic attack (such as DNA, protein and mitochondrial membrane potential destruction). The triple-hybrid ionic iridium (III) complex can reduce the toxicity to healthy cells and improve the patient tolerance through the rigid ligand to regulate selectivity. The pyridine group and the biphenyl group in the rigid C^N ligand can be further modified (such as introducing an alkyl chain, a halogen atom and a functional group) to further regulate the redox potential, the excited state lifetime and the biological distribution characteristics of the complex, and the toxicity and universality of the complex to tumor cells can be further improved.

[0025] Further, by selecting different C 1 ^N 1 ligands, C 2 ^N 2 ligands and P^P ligands, a series of novel triple-hybrid ionic iridium (III) complexes with different structures and properties can be obtained through ligand flexible regulation, and an innovative idea is provided for the research and development of novel anti-tumor drugs in the biological and medical fields.

[0026] The drug composition provided by the application has a unique chemical structure and biological activity, and can interact with specific targets in tumor cells to play an anti-tumor role. When the triple-hybrid ionic iridium (III) complex with double-phosphine ligands is prepared into a drug composition, the complex can synergistically act with other components to inhibit the growth and proliferation of tumor cells through multiple pathways. Through reasonable selection and collocation, the complex can be released or controlled to make the drug continuously play a role in the tumor site, prolong the action time of the drug and improve the curative effect.

[0027] The application provided by the application, the iridium (III) center in the complex can synergistically exert the antitumor activity with the bisphosphine ligand, the iridium (III) center is combined with DNA / RNA, the bisphosphine ligand targets the tumor cell surface receptor or inhibits the bone resorption related signal pathway in the tumor microenvironment, forms the "metal-ligand" synergistic anticancer mechanism, and the cytotoxicity and targeting of the ligand are optimized by regulating the structure, so that candidate molecules are provided for the development of new anticancer drugs; the bisphosphine ligand is sensitive to the acidic tumor microenvironment (pH 6.5-7.0), and can specifically release iridium ions at the lesion, thereby reducing the toxicity to normal tissues (pH 7.4). Different from the action mechanism of traditional platinum drugs such as cisplatin, the iridium (III) complex is not easy to be expelled by multidrug resistance proteins (such as P-gp), can overcome tumor drug resistance, and improves the treatment effect of recurrent tumors. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The application is based on the three-hybrid ionic iridium (III) complex S1 containing a bisphosphine ligand 1 H NMR spectrum Figure 2 The application is based on the three-hybrid ionic iridium (III) complex S1 containing a bisphosphine ligand and the bisphosphine dihybrid complex S2 containing a ligand. DETAILED DESCRIPTION

[0029] In order for those skilled in the art to better understand the application scheme, the technical solutions in the embodiments of the application will be clearly and completely described below in combination with the drawings in the embodiments of the application. Obviously, the described embodiments are only a part of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor should belong to the protection scope of the application.

[0030] In the embodiments, the specific experimental steps or conditions are not specified, and the operation or conditions can be performed according to the conventional experimental steps described in the literature in the art. The reagents or instruments used are not specified by the manufacturer, and are all conventional reagent products that can be obtained by purchase.

[0031] In the application, if no special description is given, the experimental raw materials used are all commercially available goods well known to those skilled in the art.

[0032] The tumor cells used in the application are lung cancer cells PC-9 and breast cancer cells MBA-MD-231 (Shanghai Tico Biotechnology Co., Ltd.).

[0033] The application uses [Ir (C 1 ^N 1 )(C 2^N 2 )(P^P)] + PF6 - Type complex S1, namely [Ir(iqbt)(ppy)(dppb)] + PF6 - For specific metal anti-tumor drugs, human lung cancer cells PC-9 and breast cancer cells MBA-MD-231 are taken as the objects of investigation, and the technical solution of the present invention is further explained so as to more fully understand the content of the patent of the present invention.

[0034] Example 1 This embodiment provides a triheterolate ion-type iridium (III) complex S1 containing a bisphosphine. The structural formula of S1 is shown below. The specific preparation process is as follows: .

[0035] (1) Synthesis of the bridging intermediate [Ir(iqbt)(ppy) (µ-Cl)]2 1-(Benzo[b]thiophen-2-yl)isoquinoline (Hiqbt), 2-phenylpyridine (ppy), and iridium chloride trihydrate in a molar ratio of 2.2:2.2:1 were added to a mixed solvent of ethylene glycol monoethyl ether and deionized water (the volume ratio of ethylene glycol monoethyl ether to deionized water was 3:1). The mixture was reacted at 110°C under a nitrogen atmosphere for 48 hours. After the reaction was completed, the mixture was cooled to room temperature and a saturated salt solution was added and stirred for 1 hour. The precipitate was collected and dried in a vacuum drying oven at 45°C for 12 hours to obtain a mixture containing the dichloro-bridged intermediate [Ir(iqbt)(ppy) (µ-Cl)]2. (2) Synthesis of iridium (III) complex S1 containing a triheterolate ion containing a diphosphine The bridged intermediate mixture and the P^P auxiliary ligand 1,2-bis(diphenylphosphino)benzene (dppb) with a molar ratio of 1:2.5 were added to a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane and methanol was 2:1). The mixture was reacted at 55°C for 24 h under nitrogen atmosphere, then cooled to room temperature. 245 mg of ammonium hexafluorophosphate was added and the mixture was stirred at 25°C for 12 h to obtain the main product, a triheterolate ion-type iridium (III) complex S1 ([Ir(iqbt)(ppy)(dppb)] + PF6 - ), and the by-product contains a diphosphine-containing heteroligand ionic complex S2 ([Ir(ppy)2(dppb)] + PF6 - ).

[0036] The iridium (III) complex S1 containing a triheterolate ion containing bisphosphine was dissolved in deuterated DMSO and subjected to NMR experiments to obtain Figure 1 H NMR spectrum: Iridium(III) complex S1 [Ir(iqbt)(ppy)(dppb)] containing a triheterolate ion + PF6 - of 1 The H NMR spectra are assigned as follows: 8.65 (m,1H,-Py), 8.29 (t,1H,-Py), 8.15 (m,3H,-Py), 8.03 (d,1H,-Ph),7.93(m,1H,-Ph), 7.83 (m,3H,-Ph), 7.71 (t,4H,-Ph), 7.61 (m,4H,-Ph), 7.52(m,4H,-Ph), 7.33 (m,3H,-Ph), 7.13 (m,2H,-Ph), 6.92 (m,6H,-Ph), 6.82 (t,1H,-Ph),6.64 (dd,1H,-Ph), 6.49 (td,2H,-Ph), 6.26 (m,5H,-Ph). By the attached Figure 1 The data shows that through 1 H NMR spectroscopy confirmed that the assignment of the characteristic resonance signals of the bisphosphine-containing triheterolate iridium(III) complex S1, a novel compound of the present invention, closely matches theoretical predictions. Specifically, 1) the chemical shift values ​​δ for each proton exhibited minimal deviation from theoretical predictions, accurately corresponding to hydrogen atoms in different chemical environments within the molecule; and 2) the integrated area ratios closely matched the ratios of the number of equivalent protons in the molecular formula. This confirmed that the stereochemical configuration of the target complex is identical to the molecular structure of the expected synthetic product S1.

[0037] Example 2 This embodiment provides a triheterolate ion-type iridium (III) complex S3 containing a bisphosphine, the structural formula of which is shown below, and the specific preparation process is as follows: .

[0038] (1) Synthesis of the bridging intermediate [Ir(dpbq)(dfppy) (µ-Cl)]2 2,3-Diphenylbenzo[g]quinoxaline (dpbq), 2-(2,4-difluorophenyl)pyridine (dfppy), and iridium chloride trihydrate in a molar ratio of 2.2:2.2:1 were added to a mixed solvent of ethylene glycol monoethyl ether and deionized water (the volume ratio of ethylene glycol monoethyl ether to deionized water was 3:1). The mixture was reacted at 110°C under a nitrogen atmosphere for 48 hours. After the reaction was completed, the mixture was cooled to room temperature and a saturated salt solution was added and stirred for 1 hour. The precipitate was collected and dried in a vacuum drying oven at 45°C for 12 hours to obtain a mixture containing the dichloro-bridged intermediate [Ir(dpbq)(dfppy) (µ-Cl)]2. (2) Synthesis of iridium (III) complex S3 containing a triheterolate ion containing a diphosphine A mixture of the bridged intermediates and the P^P auxiliary ligand 1,2-bis(diphenylphosphino)ethane (dppe) at a molar ratio of 1:2.5 was added to a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane to methanol was 2:1). The mixture was reacted at 55°C for 24 h under nitrogen atmosphere, then cooled to room temperature. 245 mg of ammonium hexafluorophosphate was added, and the mixture was stirred at 25°C for 12 h to obtain the product, a triheterolate ion-type iridium (III) complex S3 ([Ir(dpbq)(dfppy)(dppe)] + PF6 - ).pass 1 H NMR spectroscopy analysis confirmed that the attribution of the characteristic resonance signals of the bisphosphine-containing triheterolate ion-type iridium (III) complex S3 of the present invention is highly consistent with theoretical predictions, and confirmed that the stereochemical configuration of the target complex is completely consistent with the molecular structure of the expected synthetic product S3. The confirmed structural formula is as follows: .

[0039] Example 3 This embodiment provides a triheterolate ion-type iridium (III) complex S4 containing a bisphosphine, the structural formula of which is shown below, and the specific preparation process is as follows: .

[0040] (1) Synthesis of the bridging intermediate [Ir(tpbz)(mppy) (µ-Cl)]2 Tribenzo[a,c,i]phenazine (tpbz), 3-methyl-2-phenylpyridine (mppy), and iridium chloride trihydrate in a molar ratio of 2.2:2.2:1 were added to a mixed solvent of ethylene glycol monoethyl ether and deionized water (the volume ratio of ethylene glycol monoethyl ether to deionized water was 3:1). The mixture was reacted at 110°C under a nitrogen atmosphere for 48 hours. After the reaction was completed, the mixture was cooled to room temperature and a saturated salt solution was added and stirred for 1 hour. The precipitate was collected and dried in a vacuum drying oven at 45°C for 12 hours to obtain a mixture containing the dichloro-bridged intermediate [Ir(tpbz)(mppy)(µ-Cl)]2. (2) Synthesis of iridium (III) complex S4 containing a triheterolate ion containing a diphosphine A mixture of the bridged intermediates and the P^P auxiliary ligand 1,3-bis(diphenylphosphino)propane (dppp) at a molar ratio of 1:2.5 was added to a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane and methanol was 2:1). The mixture was reacted at 55°C for 24 h under nitrogen atmosphere, then cooled to room temperature. 245 mg of ammonium hexafluorophosphate was added, and the mixture was stirred at 25°C for 12 h to obtain the product, a triheterolate ion-type iridium (III) complex S4 ([Ir(tpbz)(mppy) (dppp)] + PF6 - ),pass 1 H NMR spectroscopy analysis confirmed that the attribution of the characteristic resonance signals of the bisphosphine-containing triheterolate ion-type iridium (III) complex S4 of the present invention is highly consistent with theoretical predictions, and confirmed that the stereochemical configuration of the target complex is completely consistent with the molecular structure of the expected synthetic product S4. The confirmed structural formula is as follows: .

[0041] Example 4 This embodiment provides a triheterolate ion-type iridium (III) complex S5 containing a bisphosphine, the structural formula of which is shown below, and the specific preparation process is as follows: .

[0042] (1) Synthesis of the bridging intermediate [Ir(iqbt)(mppy) (µ-Cl)]2 1-(Benzo[b]thiophen-2-yl)isoquinoline (IQBT), MPPY, and iridium chloride trihydrate in a molar ratio of 2.2:2.2:1 were added to a mixed solvent of ethylene glycol monoethyl ether and deionized water (the volume ratio of ethylene glycol monoethyl ether and deionized water was 3:1), and the mixture was reacted at 110°C under a nitrogen atmosphere for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated salt solution was added and stirred for 1 hour, and the precipitate was collected and dried in a vacuum drying oven at 45°C for 12 hours to obtain a mixture containing the dichloro-bridged intermediate [Ir(IQBT)(MPPY)(µ-Cl)]2; (2) Synthesis of iridium (III) complex S5 containing a triheterolate ion containing a diphosphine A mixture of the bridged intermediates and the P^P auxiliary ligand 1,2-bis(diphenylphosphino)benzene (dppb) at a molar ratio of 1:2.5 was added to a mixed solvent of dichloromethane and methanol (the volume ratio of dichloromethane and methanol was 2:1). The mixture was reacted at 55°C for 24 h under nitrogen atmosphere, then cooled to room temperature. 245 mg of ammonium hexafluorophosphate was added, and the mixture was stirred at 25°C for 12 h to obtain the product, a triheterolate ion-type iridium (III) complex S5 ([Ir(iqbt)(mppy)(dppb)] + PF6 - ),pass 1HNMR spectrum analysis confirmed that the characteristic resonance signal attribution of the iridium (III) complex S5 containing bisphosphine trihetero ligand ion type in the application was highly consistent with the theoretical prediction, the stereochemical configuration of the target complex was completely consistent with the molecular structure of the expected synthesis product S5, and the structural formula was as follows: .

[0043] II. Performance test On the basis of examples 1~4, the toxicity experiment of lung cancer cell PC-9 and breast cancer cell MBA-MD-231 on the iridium (III) complex S1 containing bisphosphine trihetero ligand ion type prepared in example 1 of the application was carried out, and the iridium (III) complex S2 containing bisphosphine dihetero ligand ion type obtained by the application was used as a control.

[0044] Cell pretreatment: the cells (PC-9 and MDA-MB-231) were digested by 0.25% trypsin-EDTA mixed solution, the cell clusters were collected by centrifugation at 1000 rpm for 5 minutes, the supernatant was removed, and 10% bovine serum culture solution was added for repeated washing; Cell counting and dilution: 100 μL of cell solution was added to a 96-well plate counting plate, the cell concentration was calculated by a hemocytometer, and the culture solution was diluted to 10000 cells / mL.

[0045] Concentration gradient design: the iridium complexes S1 and S2 were set to have 0, 1.25, 2.5, 5, 10 and 20 μM, and 4~6 replicates were set for each concentration.

[0046] Drug treatment and detection: the cell suspension was inoculated into a 96-well plate and incubated in an incubator (37℃, 5% CO2) for 24 h; different concentrations of iridium complexes were added, and after 24 h of culture, 15 μL of 5.0 mg / mL MTT solution was added to each well, and the black condition incubator was continued to be cultured for 4~6 h; the supernatant in the plate was poured off, 100 μL of DMSO was added to each well, and oscillation was performed for 6 min; the absorbance (OD value) was detected at 570 nm by using an enzyme-labeled instrument, and the survival rate (%) of the iridium complex on different tumor cells was calculated according to formula (1), (1) Among them, the culture solution+MTT+DMSO group was used as a blank control, and the cell well without adding iridium complex drug treatment was used as a control group.

[0047] Referring to the attached Figure 2 IC 50 value comparison: the IC 50 of the iridium (III) complex S1 containing bisphosphine trihetero ligand ion type in the application on PC-9 cells was 0.9±0.04 μM, which was significantly lower than the IC 50= 1.4±0.11μM (P<0.01); IC of the bisphosphine-containing triheterolactic ion-type iridium (III) complex S1 against MBA-MD-231 cells 50 The value was 0.9 ± 0.07 μM, which was significantly lower than the IC of S2. 50 = 1.9±0.23 μM (P<0.01), indicating that the inhibitory efficiency of S1 on both tumor cells was significantly higher than that of S2, and the IC 50 The values ​​are close, indicating that the effect is stable.

[0048] Dose-effect relationship: Within the concentration range of 0-20 μM, cell survival rate decreased significantly with increasing S1 concentration (both PC-9 and MDA-MB-231 cells showed a clear trend). At the same concentration, S2 had a significantly higher cell survival rate than S1 (e.g., at 20 μM, the survival rate of the S1-treated group was close to 0%, while that of the S2-treated group was still >20%).

[0049] Cell-wide applicability analysis: IC of S1 in PC-9 (lung cancer cells) and MDA-MB-231 (breast cancer cells) 50 The values ​​were almost the same, indicating that its inhibitory effect was not restricted by cell type; the IC 50 The value was significantly higher than that in PC-9 cells (1.9 μM vs. 1.4 μM).

[0050] It can be seen that S1 is significantly better than the byproduct S2 in IC 50 In the concentration range of 0-20 μM, the inhibitory effect of S1 on tumor cells increased significantly with increasing concentration. Furthermore, a comparison of the experimental results of S1 and S2 revealed that S1 has certain advantages in terms of universality against tumor cell types.

[0051] In summary, the present invention synthesizes a new type of iridium (III) complex containing a triheterolate ion of bisphosphine through innovative molecular design. In particular, the introduction of a large rigid ligand enhances the stability of the complex, allowing it to maintain structural integrity in complex physiological environments, thereby ensuring the stability of the drug. This structural advantage also makes the drug's transport and absorption in the body more efficient, significantly improving bioavailability. In terms of cytotoxicity, the complex exhibits strong inhibitory activity against various tumor cell lines, and its IC activity against most tumor cell types is 1.54. 50The value is far lower than that of traditional Ir(C^N)2(P^P)-type bisphosphine-containing heteroleptic drugs, demonstrating its excellent toxicity and universal applicability. These advantages make the bisphosphine-containing triheterolactic ion-type iridium (III) complex of the present invention a promising new anticancer metallodrug with stable, efficient and good bioavailability, and has great potential and broad application prospects in the future field of anticancer treatment.

[0052] The above content is only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A trihybrid ionic iridium (III) complex containing a diphosphine ligand, characterized in that: The tri-hybrid ionic iridium (III) complex has the following structural formula: ； Among them, C 1 ^N 1 The ligand is selected from any one of the rigid ligands Hiqbt, dpbq and tpbz; C 2 ^N 2 The ligand is selected from any one of ppy, dfppy and mppy ligands; The P^P ligand is selected from any one of a rigid group or a flexible group, wherein the rigid group is a phenyl group or a naphthyl group, and the flexible group is an ethylene group or a propylene group.

2. A trihybrid ionic iridium (III) complex containing a diphosphine ligand according to claim 1, characterized in that: The P^P ligand is any one of 1,2-bis(diphenylphosphino)benzene, 1,2-bis(diphenylphosphino)ethane, and 1,3-bis(diphenylphosphino)propane.

3. A trihybrid ionic iridium (III) complex containing a diphosphine ligand according to claim 1, characterized in that: The tri-hybrid ionic iridium (III) complex has the following structural formula: 。 4. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the trihybrid ionic iridium (III) complex containing a bisphosphine ligand according to any one of claims 1 to 3.

5. A pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition further includes a pharmaceutically acceptable carrier.

6. A pharmaceutical composition according to claim 5, characterized in that The carrier is selected from fillers, disintegrants, binders, lubricants or combinations thereof.

7. Use of a trihybrid ionic iridium (III) complex containing a bisphosphine ligand according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 to 6 in the preparation of an antitumor drug.

8. The use according to claim 7, characterized in that The tumor is any one or more of lung cancer, breast cancer, liver cancer, stomach cancer, colon cancer, prostate cancer, and ovarian cancer.

9. The use according to claim 7, characterized in that The anti-tumor drug is used to inhibit the proliferation of tumor cells.

10. The use according to claim 7, characterized in that The anti-tumor drug is used to induce apoptosis of tumor cells.

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